The objective of this application is to understand the mechanisms responsible for coronary sclerosis and cardiac dysfunction induced by total body irradiation (TBI), and to identify and develop medical countermeasures to mitigate and/or treat such injury. Our preliminary studies indicate that 10 Gy single-dose TBI, a dose and schedule relevant to radiological terrorist attacks and nuclear accidents, is associated with the development of risk factors for cardiovascular disease, coronary sclerosis and functional injury to the heart. Furthermore, the pharmaceutical Losartan and the nutriceutical curcumin appear to prevent TBI-induced development of risk factors for cardiovascular disease. Whereas there is a substantial body of literature regarding the impact of TBI in organs such as the intestine and kidney, there is no information about the mechanisms by which TBI causes injury to the heart. The sequence of the molecular and cellular events that result in coronary sclerosis and ventricular dysfunction following TBI is not known. We hypothesize that TBI-induced damage to the heart results from increased risk factors for cardiovascular disease. The corollary to this hypothesis is that pharmaceutical treatments that decrease risk factors for cardiovascular disease will be effective in treating TBI-induced coronary sclerosis and ventricular dysfunction. This hypothesis will be tested in an established rat bone marrow transplant model. Three specific aims will be tested: Specific Aim 1 will determine the extent that TBI results in an imbalance between procoagulant and anticoagulant function of the vasculature resulting in coronary sclerosis and ventricular dysfunction. Specific Aim 2 will determine the mechanisms by which TBI indirectly injures the coronary vasculature/endothelium to decrease nitric oxide and increases superoxide production from nitric oxide synthase. Specific Aim 3 will determine the ability of a medical countermeasure to mitigate or treat TBI induced injury to the cardiovascular system when given after radiation exposure. These studies will define mechanisms underlying TBI- induced injury to the coronary vasculature and ventricular function and determine the ability of existing pharmaceuticals countermeasures to mitigate and/or treat radiation-induced injury to the cardiovascular system. 1